{"paper_id":"937150ee-5eaf-4f69-be5a-33eb0cc8df87","body_text":"R E S E A R C H Open Access\nThe effectiveness of nonsteroidal anti-inflammatory\nagents in the treatment of pelvic inflammatory\ndisease: a systematic review\nDivya Dhasmana 1*, Emma Hathorn 1, Racheal McGrath 1, Anjum Tariq 2 and Jonathan DC Ross 1\nAbstract\nBackground: Pelvic inflammatory disease (PID) is the result of infection ascending through the endocervix to the\nuterus and fallopian tubes. Inflammation driven by infected host cells appears to be central to the development of\ntissue damage and associated reproductive complications. Nonsteroidal anti-inflammatory agents (NSAIDs) therefore\nhave the potential to reduce the sequelae associated with pelvic infection.\nMethods: A search of four electronic reference databases, an internet search for relevant grey literature and a\nreview of the bibliographies of identified publications was used to identify studies evaluating NSAIDs in the\nmanagement of PID. A predefined search strategy was used to identify studies that included women with PID aged\nover 16 and diagnosed after 1980. Randomized controlled trials, nonrandomized controlled trials, and cohort\nstudies with comparison group data were included without language restriction. Two reviewers independently\nassessed the studies against agreed criteria and extracted relevant data using a standardized pro forma. A\nmeta-analysis to calculate the relative risk associated with NSAID use was planned if appropriate.\nResults: Forty-three studies were identified. After reviewing abstracts or full texts, two randomized controlled trials\nwere found to meet the selection criteria for inclusion. The use of NSAIDs was reported to improve tubal patency,\nreduce pelvic adhesions and reduce suprapubic pain but the studies were of poor quality with a high risk of bias.\nMeta-analysis of the data was not performed.\nConclusions: Insufficient data is available to support or refute the efficacy of NSAIDs in the prevention of short or\nlong-term complications of PID.\nKeywords: nonsteroidal anti-inflammatory drugs, pelvic inflammatory disease, systematic review\nBackground\nPelvic inflammatory disease (PID) is an infectious and\ninflammatory disorder of the uterus, fallopian tubes and\nadjacent pelvic structures as a result of ascending infec-\ntion from the endocervix. The highest prevalence is in\n16- to 24-year-olds, reflecting the high rate of bacterial\nsexually transmitted infections found in this age group [1].\nComplications include infertility, ectopic pregnancy and\nchronic pelvic pain, and can result in considerable physical\nand emotional morbidity, in addition to a significant fi-\nnancial burden on healthcare services.\nChlamydia trachomatis and Neisseria gonorrhoeae are\nthe causative agents in approximately 40% of cases of PID\n[2]. Mycoplasma genitalium, Trichomonas vaginalis, Herpes\nsimplex type 2, bacterial vaginosis-associated microorgan-\nisms and anaerobic organisms endogenous to the vaginal\nflora have also been isolated from the upper genital tract,\nalthough their role in the reproductive complications of\npelvic infection remains unclear [3-8]. Inflammation\ndriven by infected host cells appears central to the de-\nvelopment of reproductive complications. Epithelial cells\nare the primary target of chlamydial infection, and are\nthought to initiate and sustain the host response through\nthe secretion of chemokines, which recruit inflammatory\nleukocytes to the site of infection, and which also induce\nand regulate the inflammatory process. For example, Toll-like\n* Correspondence: divya.dhasmana@nhs.net\n1Department of Genitourinary Medicine, Whittall Street Clinic, Whittall Street,\nBirmingham B4 6DH, UK\nFull list of author information is available at the end of the article\n© 2014 Dhasmana et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the\nCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public\nDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this\narticle, unless otherwise stated.\nDhasmana et al. Systematic Reviews 2014, 3:79\nhttp://www.systematicreviewsjournal.com/content/3/1/79\n\nreceptor-2 acts as a mediator of the innate immune re-\nsponse and has a role in both the production of inflamma-\ntory mediators and the development of upper genital tract\npathology [9].\nThe adaptive immune response is also triggered by the\nrelease of inflammatory mediators. The CD4 Th-1 re-\nsponse is thought to be the main mechanism of infection\nresolution. Reinfection is common and it is proposed that\nan amplified Th-1 response to chronic or repeat infection\nmight promote tissue damage and scarring. Chlamydia\nheat shock protein-60 (Chsp60) has been investigated as\nthe possible cause of a delayed hypersensitivity reaction\nleading to a heightened inflammatory response. It has a\nhighly conserved amino acid sequence, chlamydial and\nhuman sequences being 48% homologous. This similar-\nity may result in an autoimmune response due to cross\nreactivity between self-hsp and Chsp-60. However, des-\npite animal data supporting this hypothesis, the PID\nEvaluation and Clinical Health (PEACH) study did not\ndemonstrate a correlation between increased antibody\ntitres to Chsp60 and PID-related complications [10]. In\ncontrast, antibodies to Chlamydia trachomatis elemen-\ntary bodies, the extracellular form of Chlamydia ,w e r e\nindependently associated with reduced rates of preg-\nnancy and elevated rates of recurrent PID at 7 years of\nfollow-up. It remains unclear whether chlamydial anti-\nbody titres simply reflect increased exposure, in terms\nof either chronicity of infection or reinfection, or if their\npresence represents a direct role in pathogenesis.\nA number of host factors and cellular responses have\nbeen associated with susceptibility or protection from the\ndevelopment of reproductive complications. For example,\nthe production of interferon- γ by peripheral blood mono-\nnuclear cells stimulated with Chsp60 has been strongly as-\nsociated with protection against new Chlamydia infection\n[11]. Host factors that regulate the Th-1 response may also\ntherefore be important in modifying the risk of long-term\ncomplications.\nCurrent treatment guidelines focus on the eradication\nof infection using a regimen of broad-spectrum antibi-\notics [12,13]. The role of surgery is limited to the early\ndivision of adhesions and drainage of pelvic collections.\nNo treatment is currently recommended to prevent or\nreduce the inflammatory process.\nNonsteroidal anti-inflammatory drugs (NSAIDs) are a\ngroup of analgesic drugs that act as nonselective inhibitors\nof the cyclooxygenase (COX) enzyme. The COX enzyme\nis required for the formation of prostaglandins that regu-\nlate the inflammatory response. There are two forms of\nthis enzyme: a constitutive form, COX-1, that is present in\nthe gastric mucosa, and an inducible form, COX-2; the\nlatter form is preferentially expressed at sites of inflamma-\ntion. Inhibition of the former leads to the well-described\ngastric side effects of NSAIDs, and inhibition of the latter\nto its therapeutic anti-inflammatory effects. Both COX-1\nand COX-2 are expressed in the uterine epithelium at dif-\nferent times in early pregnancy [14], whilst COX enzymes\nare also known to be involved in endometrial pathology\n[15]. Animal studies have demonstrated that the immu-\nnoexpression of COX-2 was found to be strongest in\nendometrium with acute endometritis compared with\nnormal endometrium or chronic endometritis [16]. In\naddition, COX-2 expression has been found to be an\nindependent prognostic factor in uterine leiomyosarco-\nmas [17].\nThe role of the COX enzyme in inflammation and adhe-\nsion formation in the murine model is well established\nand provides a mechanism for NSAIDs, through COX\ninhibition, to affect PID outcomes. Trauma to rat paws\nhas been shown to induce expression of COX-2 and in\nturn increase the production of prostaglandin, resulting\nin oedema and a hyperalgesic response [18]. This path-\nway was blocked following the selective inhibition of\nCOX-2 with indomethacin. Furthermore, following the\ninduction of peritoneal fibrosis in rats, provision of NSAID\nwas shown to reduce the extent and severity of adhesions\nin comparison with intraperitoneal saline or placebo [19].\nNonsteroidal anti-inflammatory drugs, commonly used\nas analgesics, may therefore provide a means of reducing\nthe inflammation and subsequent fibrosis that leads to\ntubal damage associated with PID and its complications.\nObjectives\nThe objective of this review was to assess the clinical effect-\niveness of NSAIDs (in addition to antibiotic therapy) in\nthe treatment of PID, including the prevention of long-\nterm sequelae.\nMethods\nSearch strategy\nA search strategy was developed and used to identify\nrelevant studies (Additional file 1). Databases were\nsearched between March and May 2011 and again in\nJune 2014 as follows: MEDLINE from PubMed 1980 to\npresent, EMBASE 1980 to present, CINAHL 1981 to\npresent and the Cochrane library. Searches were repeated\nin grey literature (Additional file 2) to identify any unpub-\nlished and ongoing research. No language restriction was\napplied.\nTwo reviewers independently searched each database,\nscanned titles and abstracts, and retrieved papers that ful-\nfilled the predefined inclusion criteria, described next. In\ncase of disagreement, a final decision on whether to include\nas t u d yw a sm a d eb yc o n s e n s u sw i t hat h i r dr e v i e w e r .\nTypes of study\nRandomized controlled trials (RCTs), nonrandomized\ncontrolled trials and cohort studies reporting data from\nDhasmana et al. Systematic Reviews 2014, 3:79 Page 2 of 6\nhttp://www.systematicreviewsjournal.com/content/3/1/79\n\na comparison group were eligible for inclusion. Case series\nand case reports were excluded.\nTypes of participant\nStudies of females 16 years or over diagnosed clinically\nwith PID as an inpatient or outpatient since 1980 were\nincluded.\nTypes of intervention\nStudies in which NSAIDs were given for the treatment\nof PID in combination with antibiotic therapy and where\ndata were also reported from a comparison group were\neligible for inclusion. The comparators included placebo\nor any intervention given in addition to antibiotic ther-\napy for the treatment of PID, including paracetamol or\nopiates.\nTypes of outcome\nShort and long-term clinical markers of effectiveness\nwere included.\nShort term outcomes:\n/C15Severity of pain.\n/C15Time to resolution of pain.\n/C15Length of inpatient stay.\nLong-term outcomes:\n/C15Chronic pelvic pain.\n/C15Tubal patency.\n/C15Tubal factor infertility.\n/C15Ectopic pregnancy.\n/C15Miscarriage.\nData extraction\nA standardized data extraction form was designed\nand, after internal review by the study team, utilized\n(Additional file 3). Two reviewers independently extracted\ndata from the articles and disagreements were resolved\nfollowing discussion. The authors of identified papers\nwere contacted to request additional information where\nrequired. Study quality was assessed using the Cochrane\nRisk-of-Bias Tool [20].\nData synthesis\nArticles were stratified by type of NSAID and compara-\ntor. Key findings were reported.\nResults\nForty-three studies were identified by the search strat-\negy. Thirty-six articles were excluded after title and ab-\nstract review, as they did not meet the predefined\ninclusion criteria. A further five articles were excluded\nafter full text or abstract review of English translations\n(three trials did not include a comparator arm [21-23],\none study compared the efficacy of two different NSAIDs\n[24] and one study did not give NSAIDs in addition to\nstandard antibiotic therapy [25]). The remaining two stud-\nies were included for data extraction. References from\nthese were reviewed for further relevant studies but none\nwere identified.\nStudy design\nThe two studies included for data extraction were RCTs.\nBassil et al. [26] randomized 40 women with acute salpin-\ngitis or PID to receive piroxicam, a nonselective COX\ninhibitor, or no NSAID in addition to antibiotic therapy.\nGoffi et al. [27] randomized 42 women with mild acute\nPID to receive fentiazac, a new NSAID, or placebo in\naddition to antibiotic therapy. The duration of follow-\nup was short in both studies (9 to 11 weeks [26] and\n10 days [27]).\nQuality\nA risk-of-bias study is outlined in Additional file 4. The\nrandomization process was not described clearly in ei-\nther of the included studies. The nature of blinding of\nthe investigator or subject to the intervention received\nwas not clearly stated in either study. Outcome mea-\nsures were not clearly defined and were often subjective.\nThe basis of some statistical calculations in both trials\nwas not reported, with only a P value provided. No add-\nitional information on study methodology, results or\nanalysis was received following approaches to the study\ninvestigators.\nOutcomes\nThe chosen outcome measures were different in each\nstudy. Bassil et al. [26] performed a repeat laparoscopy\nat 9 to 11 weeks after the start of treatment and evalu-\nated residual inflammation on inspection, peritoneal cy-\ntology, histological study of adhesions and tubal patency\n(categorized as mild, moderate or severe). These findings\nformed the basis of a subjective prognosis regarding fer-\ntility for each woman. In contrast, the primary outcome\nreported by Goffi et al . [27] was subjective resolution of\nadnexal pain on bimanual examination, or suprapubic\nand iliac fossa pain on palpation.\nThe key findings from the included studies are summa-\nrized in T able 1. A meta-analysis was not performed,\nowing to the heterogeneity and low methodological qual-\nity of the identified studies.\nDiscussion\nEffectiveness of NSAIDs\nThe studies included in this review provide insufficient\ndata to support the use of NSAIDs in the prevention of\nlong-term complications of PID. The use of NSAIDs was\nDhasmana et al. Systematic Reviews 2014, 3:79 Page 3 of 6\nhttp://www.systematicreviewsjournal.com/content/3/1/79\n\nreported as reducing tubal obstruction, residual adhesions,\npain and overall symptoms but the studies had limited\npower and were of low quality.\nA role for NSAIDs in the reduction of inflammation\nand prevention of adhesions, through COX-2 inhibition,\nhas been demonstrated in animal models but there is no\ncomparable data for their effectiveness in altering the clin-\nical course of inflammatory conditions in human subjects.\nFor example, there is no evidence to suggest that NSAIDs\nmodify the course of rheumatoid arthritis, where their ef-\nfect is limited to symptomatic benefit [28]. Furthermore,\nthe regular use of NSAIDs has to be balanced against their\nsignificant adverse effects including gastrointestinal haem-\norrhage, renal impairment and interactions with other\ncommonly prescribed medication.\nInflammation appears to be central to the development\nof complications associated with PID and therefore other\nagents that modulate the immune system, including corti-\ncosteroids and biological immune modulators, might have\na role in their prevention. Sanfilippo [29], in a case control\nstudy that involved incision and eversion of rat proximal\nuterine horns, treated the animals pre- and postoperatively\nwith either corticosteroid or normal saline injections. Beta-\nmethasone phosphate produced a significant reduction in\nfibrosis when compared with all other corticosteroids or\ncontrol solutions.\nQuality of included studies\nA small number of individuals were included, with a total\nof only 82 patients identified from two studies. The marked\ndifferences between trials in antibiotic regimen used, treat-\nment intervention and outcome measures meant that it\nwas inappropriate to pool data for analysis. Both studies\nwere described as RCTs but neither described their method\nof generating a random allocation sequence, their method\nof allocation concealment or who was blinded to the allo-\ncation schedule. A single operator was used to perform the\nsecond-look laparoscopies in the Bassil study [26] in an at-\ntempt to reduce inter-observer variability in reporting. It is\nnot stated, however, whether the operator was blinded to\nt h ei n t e r v e n t i o nr e c e i v e d .I nt h eG o f f is t u d y[ 2 7 ] ,t h e r ew a s\nno description of the placebo drug and how it compared in\nappearance and method of administration to fentiazac. The\npain assessment was not validated and, in view of the sub-\njective nature of pain and its reporting, inadequate blinding\nmay have introduced bias.\nThe antibiotic therapy regimen given to women varied\nconsiderably between studies and was suboptimal when\nTable 1 Summary of included studies\nStudy\ndesign\nPopulation Size Antibiotics Control Intervention Analysis Key findings\n[26] RCT Acute\nsalpingitis\nor PID\n40 Co-amoxiclav 1 g three times daily\ndoxycycline 200 mg once daily\nintravenously for 5 days followed by\nco-amoxiclav 500 mg three times\ndaily for 15 days and doxycycline\n200 mg once daily for 21 days\nNo\nNSAID\nPiroxicam\n20 mg/day\nfrom day 3\npost-operation\nfor 25 days\nPer\nprotocol\nTubal patency: in severe PID,\nbilateral patency was seen in 1/7\n(14.2%) of placebo group versus 7/9\n(77.8%) of intervention group\n(P = 0.02, Fisher’s exact test)\nConfirmed\nby\nlaparoscopy\nResidual adhesions: in severe PID,\nmore patients in intervention group\nhad no residual adhesions, 6/9\n(66.7%), versus control group, 1/7\n(14.3%) (P = 0.06, Fisher’s exact test)\nNo difference between arms in tubal\npatency or residual adhesions for\nmild or moderate PID\n[27] RCT Mild acute\nPID\n42 Tetracycline 500 mg four times daily\nfor 10 days\nPlacebo Fentiazac\n200 mg twice\ndaily for 7 days\nIntention\nto treat\nSuprapubic pain: resolution of pain\noccurred by day 7 in 9/21 (43%) of\npatients in the intervention group\nversus 5/21 (24%) in the control\ngroup (P = 0.2, χ square)\nClinical\ndiagnosis\nReduction in overall signs and\nsymptoms: greater reduction in\naverage score for severity of signs\nand symptoms in the intervention\ncompared with the placebo group\n(figures providing the basis of the\ncalculation not provided)\nNausea reported in 4/21 patients\nreceiving fentiazac (1 discontinuation)\nversus 2/21 in the control group (no\ndiscontinuations)\nNSAID nonsteroidal anti-inflammatory drug; PID pelvic inflammatory disease; RCT randomized controlled trial.\nDhasmana et al. Systematic Reviews 2014, 3:79 Page 4 of 6\nhttp://www.systematicreviewsjournal.com/content/3/1/79\n\ncompared with current management guidelines. European\nand American guidelines recommend the use of broad-\nspectrum antibiotics to cover Neisseria gonorrhoeae, Chla-\nmydia trachomatis , and aerobic and anaerobic bacteria\ncommonly isolated from the upper genital tract. It is\ntherefore unclear to what extent a suboptimal antibiotic\nregimen might have contributed to the reported clinical\noutcomes, including the persistence of pain and inflam-\nmation, although if randomization was robust then this\nshould not have introduced systematic bias. The poten-\ntial for bias is summarized in Additional file 4.\nPatients included in the Bassil study [26] underwent an\ninitial laparoscopy during which their presenting diagnosis\nwas confirmed. This initial procedure enabled adhesioly-\nsis, drainage of abscesses and peritoneal cavity lavage to\nbe performed. Bessil et al. [26] concluded that a signifi-\ncantly greater number of those with severe PID treated\nwith NSAIDs had fewer residual adhesions and a higher\nrate of tubal patency at second-look laparoscopy. Whilst\nthe interventions performed during the initial laparoscopy\nwere undertaken in both intervention and control groups,\nthis would not be routinely performed in clinical practice\nand may limit the generalizability of the results.\nGoffi et al. [27] reported a significant reduction in supra-\npubic pain in the group receiving a NSAIDs, compared\nwith the control group. However, the basis of the statistical\ncalculation was not clear from the data presented.\nStrengths and weaknesses\nThis is the first systematic review of the effectiveness of\nNSAIDs in the treatment of PID. A comprehensive litera-\nture review including grey literature and unrestricted by\nlanguage was performed but it remains possible that rele-\nvant studies were missed. All relevant identified articles\nwere obtained. The review complied with and is reported\naccording to PRISMA guidelines(Additional file 5). English\ntranslations were obtained for foreign language papers,\nincluding both studies included in the analysis, and a\nnumber of studies were excluded based on translations\nof abstracts.\nConclusions\nThere is insufficient data to support a recommendation\nfor routine use of NSAIDs in the management of PID\nto reduce inflammatory complications. Further RCTs\nincorporating currently recommended antibiotic regimens\nwith objective short and long-term outcome measures are\nneeded to inform any change in clinical practice.\nKey findings\nInflammation is considered central to the development\nof acute and chronic reproductive complications of PID.\nNSAIDs are used in the management of PID. Animal\nstudies indicate that NSAIDs may reduce inflammation\nand fibrosis.\nThere is insufficient data to support or refute the efficacy\nof NSAIDs in preventing the complications of PID.\nAdditional files\nAdditional file 1: Search strategy.\nAdditional file 2: Grey literature search.\nAdditional file 3: Data extraction form.\nAdditional file 4: Risk-of-bias summary.\nAdditional file 5: PRISMA checklist.\nAbbreviations\nCOX: cyclooxygenase; NSAID: nonsteroidal anti-inflammatory agent;\nPEACH: PID Evaluation and Clinical Health; PID: pelvic inflammatory disease;\nPRISMA: preferred reporting items for systematic reviews and meta-analyses;\nRCT: randomized controlled trial.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthors’ contributions\nJDCR conceived the idea for study, analyzed the data and helped draft the\nmanuscript. DD performed the literature search, analyzed the data and\ndrafted the overall manuscript. EH performed the literature search, analyzed\nthe data and helped draft the manuscript. RM translated foreign language\narticles and helped draft the manuscript. AT helped draft the manuscript. All\nauthors read and approved the final manuscript.\nAcknowledgements\nThe author wish to thank the Queen Elizabeth Hospital Birmingham Library\nstaff, the staff at the British Library and the British Bulgarian Society for their\ninvaluable assistance.\nAuthor details\n1Department of Genitourinary Medicine, Whittall Street Clinic, Whittall Street,\nBirmingham B4 6DH, UK. 2Department of Genitourinary Medicine, The Fowler\nClinic, New Cross Hospital, Wolverhampton WV10 0QP, UK.\nReceived: 13 January 2014 Accepted: 10 June 2014\nPublished: 22 July 2014\nReferences\n1. Simms I, Stephenson JM: Pelvic inflammatory disease: what do we know\nand what do we need to know? Sex Transm Infect 2000, 76:80–87.\n2. 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Journal de Gynecologie Obstertriqu et Biologie de la\nReproduction 1991, 20(8):1063–1067.\n27. Goffi PS, Aguiar LF, Vara ASM, Candido De Almeida Moraes FCdA: Fentiazac\nin pelvic inflammatory disease: double-blind, randomised, placebo-controlled\nstudy in ambulatory patients.Folha Med 1989, 98(4):241–246.\n28. National Institute for Health and Care Excellence: Rheumatoid Arthritis in\nAdults. http://guidance.nice.org.uk/CG79/Guidance/pdf/English.\n29. Sanfilippo JS, Cox JG, Nealon NA, Barrows GH: Comparison of\ncorticosteroid therapy in the prevention of pelvic tissue reaction and\nadhesion formation. Int J Fertility 1986, 30(4):57–67.\ndoi:10.1186/2046-4053-3-79\nCite this article as: Dhasmana et al. : The effectiveness of nonsteroidal anti-\ninflammatory agents in the treatment of pelvic inflammatory disease: a\nsystematic review. Systematic Reviews 2014 3:79.\nSubmit your next manuscript to BioMed Central\nand take full advantage of: \n• Convenient online submission\n• Thorough peer review\n• No space constraints or color figure charges\n• Immediate publication on acceptance\n• Inclusion in PubMed, CAS, Scopus and Google Scholar\n• Research which is freely available for redistribution\nSubmit your manuscript at \nwww.biomedcentral.com/submit\nDhasmana et al. Systematic Reviews 2014, 3:79 Page 6 of 6\nhttp://www.systematicreviewsjournal.com/content/3/1/79","source_license":"CC0","license_restricted":false}